Hao-Cheng Weng

Trophoblast cell surface antigen 2 (TROP2) is highly expressed in multiple cancers relative to normal tissues, supporting its role as a target for cancer therapy. OBI-992 is an antibody-drug conjugate (ADC) derived from a novel TROP2-targeted antibody linked to the topoisomerase 1 (TOP1) inhibitor exatecan via an enzyme-cleavable hydrophilic linker, with a drug-antibody ratio of 4. This study evaluated and compared the antitumor activity of OBI-992 with that of benchmark TROP2-targeted ADCs datopotamab deruxtecan (Dato-DXd) and sacituzumab govitecan (SG) in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. OBI-992 treatment exhibited statistically significant antitumor activity versus controls at doses of 3 and 10 mg/kg in various CDX and PDX models, demonstrating comparable or better antitumor activity with benchmark ADCs. In a large-tumor model, longer survival times were observed in OBI-992-treated mice compared with Dato-DXd-treated mice. OBI-992 treatment induced marked bystander killing of TROP2-negative cells in the presence of nearby TROP2-positive cells in both in vitro and in vivo studies. In lung adenocarcinoma CDX models with overexpression of either P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) to mimic ATP-binding cassette transporter-mediated multidrug resistance, OBI-992 treatment maintained antitumor activity when Dato-DXd treatment became less effective. The combination of OBI-992 at suboptimal doses with either poly (ADP-ribose) polymerase (PARP) inhibitors or an immune check point inhibitor produced synergistic antitumor effects in mouse models. Taken together, these translational results support further development of OBI-992 as a cancer therapy.

OBI-992, a novel TROP2-targeted antibody-drug conjugate (ADC), is composed of an anti-TROP2 antibody conjugated to exatecan, a topoisomerase 1 inhibitor, via an enzyme-cleavable hydrophilic linker. The stability, pharmacokinetics, pharmacodynamics, and off-target toxicity of OBI-992 were evaluated and compared with a benchmark ADC, datopotamab deruxtecan (Dato-DXd). OBI-992 exhibited better stability in human and monkey serum than Dato-DXd, which was further supported by in vivo PK study in rats. OBI-992 displayed a favorable pharmacokinetic profile compared with Dato-DXd in non-small cell lung cancer cell line-derived xenograft mouse models (NCI-H1975 and NCI-H1975/C797S), with lower clearance, longer half-lives of ADC in serum, and higher exposure of payload in tumor. The higher level of breast cancer resistance protein expression was detected in NCI-H1975/C797S cells, which may contribute better antitumor activity of OBI-992 compared with Dato-DXd as DXd is a much better substrate to breast cancer resistance protein than exatecan. The levels of the payload of OBI-992 in nontarget organs were lower or comparable with Dato-DXd. In addition, OBI-992 exhibited lower toxicity compared with Dato-DXd in the monocytic cell line THP-1 and differentiated neutrophils. Furthermore, in the Good Laboratory Practice toxicity study with cynomolgus monkeys, the highest nonseverely toxic dose was determined to be ≥60 mg/kg. Major toxicities were target-related skin lesions and reduced reticulocytes, which were reversible during recovery period. These results support further clinical development of OBI-992 for the treatment of TROP2-expressing cancers, which is currently in a phase 1 clinical trial (NCT06480240).

Aims: Incidence of intrahepatic cholangiocarcinoma (ICC) rises in western countries. However, unlike hepatocellular carcinoma, the morbidity and mortality of ICC still remains unchanged. So far, only few studies focus on the biological characteristics ICC. TGF-β1 plays a dual role in the progression of human cancer and has been implied to be a major force in ICC. In the present study, we investigated the role of TGF-β1 canonical and non canonical signaling pathways in ICC.

Background: TGF-beta plays dual roles in progression of human cancer. In precancerous stages, TGF-beta acts as tumor suppressor by providing cytostatic downstream signaling, whereas in late cancer stages, it induces processes that support tumor progression, including stroma fibroblast activation, epithelial mesenchymal transition and metastasis. Due to the high complexity of the TGF-beta signaling pathway, molecular details of this dramatic functional switch are only poorly understood. Recently, a shift from Smad2/3 C-terminal to linker site phosphorylation was hypothesized as key event for the cancer facilitating outcome of TGF-beta in colorectal and hepatocellular carcinoma. In the present study, we investigated this assumption in gastric adenocarcinoma.